CN108273065B

CN108273065B - Ophthalmic composition

Info

Publication number: CN108273065B
Application number: CN201810366640.2A
Authority: CN
Inventors: 法拉斯·斯蒂尔
Original assignee: Drug Delivery Solutions Ltd
Current assignee: MC2 Therapeutics Ltd
Priority date: 2011-03-14
Filing date: 2012-03-14
Publication date: 2020-07-31
Anticipated expiration: 2032-03-14
Also published as: RU2639472C2; AU2012228273B2; WO2012123515A1; DK2686017T3; HRP20191711T1; JP6105494B2; CN108273065A; JP2014509602A; ES2736256T3; BR112013023458A2; CA2829164C; PL2686017T3; RU2013145709A; US9610245B2; EP2686017A1; CA2829164A1; BR112013023458B1; CN103533962A; US20130345150A1; US10154959B1

Abstract

The present invention provides an ophthalmic composition comprising a polyaphron dispersion. The ophthalmic compositions improve patient compliance and/or reduce side effects after administration.

Description

Ophthalmic composition

The application is a divisional application with the application date being 2012, 03, 14 and entitled "an ophthalmic composition" No. 201280013225. X.

Technical Field

The present invention relates to ophthalmic compositions, in particular to topical ophthalmic compositions comprising polyaphron dispersions. The invention also relates to a method for preparing an ophthalmic composition, the use of the ophthalmic composition in the treatment of the human and/or animal eye by topical administration. The invention further relates to a device for dispensing an ophthalmic composition drop by drop.

Background

Ophthalmic compositions for ocular treatment are known in the art. Such compositions may, for example, contain a pharmaceutically active agent and may be used for the treatment of a particular disease of the eye. Alternatively, or in addition, the composition may be used as a tear substitute solution.

When ophthalmic compositions comprise pharmaceutically active agents and/or excipients, side effects are sometimes observed after topical application of the compositions to the eye. Such side effects may be related to the dosage and/or duration of treatment and/or efficacy of the active agent. In addition, if a sufficient (e.g., therapeutically active amount) of the active agent is not able to penetrate the eye after treatment, the efficacy of the treatment may be reduced. For example, if the composition is not sufficiently viscous after application to the eye, it may flow out of the eye before a therapeutically effective amount of the active agent penetrates the surface of the eye. Alternatively and/or additionally, the effectiveness of the treatment may be reduced if the concentration of the pharmaceutically active agent in the composition is low, so multiple therapeutic doses must be administered in order to provide a therapeutically effective amount of the agent to the patient. In such cases, the efficacy of the treatment will depend on the end user following the particular treatment regimen. This may not be desirable as end users who comply with such a regimen may be less than adequate.

Disclosure of Invention

It is an object of the present invention to overcome or solve the problems of the prior art ophthalmic compositions, or at least to provide a commercially useful alternative. An alternative and/or additional object is to provide ophthalmic compositions that are less costly and/or more effective to prepare than known ophthalmic compositions.

In a first aspect of the present invention, there is provided an ophthalmic composition comprising a polyaphron dispersion. Preferably, the ophthalmic composition is for topical administration to human and/or animal eyes. Preferably, it is a topical ophthalmic composition.

The invention will now be further described. In the following paragraphs, the different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

In a further aspect of the invention, there is provided the use of an ophthalmic composition according to any one of the preceding claims in the treatment of human and/or animal eyes by topical administration.

In a further aspect of the present invention, there is provided a method of preparing an ophthalmic composition described herein, comprising the steps of:

(i) providing a hydrophilic solvent;

(ii) providing a hydrophobic solvent;

(iii) mixing a hydrophilic solvent with a hydrophobic solvent under suitable conditions to form a composition comprising a polyaphron dispersion;

wherein the hydrophilic solvent and/or the hydrophobic solvent comprises a surfactant; wherein the hydrophilic solvent and/or the hydrophobic solvent optionally comprises a pharmaceutically active agent.

In a further aspect of the invention, there is provided a device for the dropwise dispensing of a composition, the device comprising a container holding a composition as described herein.

It is an object of the present invention to provide an ophthalmic composition which improves patient compliance and/or reduces side effects after administration compared to known compositions. It is also desirable to provide ophthalmic compositions comprising a pharmaceutically active agent, wherein the penetration of the pharmaceutically active agent from the ophthalmic composition is greater than the penetration of the pharmaceutically active agent from known ophthalmic compositions after treatment of a patient with the ophthalmic composition.

Certain advantages of the use of polyaphron dispersions in ophthalmic compositions described herein over known ophthalmic compositions, in particular over those comprising emulsions, can be summarized as follows:

● lower surfactant levels

● improved safety

● higher oil level

● simpler and more controllable preparation

● more consistent form-easy to characterize for the desired standard

● controllable and consistent drop size

● wider choice of oils

● each in its own oil

● improved stability of labile pharmaceutically active agents

● controlled rheology independent of dispersion formulation

● lower preservative levels

● consistent droplet size after extensive dilution

The present inventors have discovered that one advantage of utilizing polyaphron dispersions in ophthalmic compositions is that droplet size (e.g., the size of the discontinuous phase), rheology, surfactant levels, and the components that make up the composition can be consistently controlled. This makes it possible to provide the end user with a composition having improved or appropriate tolerability (tolerability). The composition may be adjusted to exclude irritants, such as high levels of surfactants, low preservatives, and/or to include beneficial components. They may also provide the possibility of forming compositions with high concentrations of pharmaceutically active agents and/or additives. This is because, for example, depending on their solubility, pharmaceutically active agents and/or additives may be present in the hydrophobic and/or hydrophilic, discontinuous and/or continuous phases of the polyaphron dispersion. This has particular application when increasing the amount of pharmaceutically active agent in the composition such that an increased level of pharmaceutically active agent is administered with each administration of the composition to the eye. This means that the frequency of administration of the composition can be reduced, which can aid in patient compliance and/or improve the therapeutic efficacy of the ocular disorder.

The ophthalmic compositions described herein also have the advantage of potentially allowing higher levels of pharmaceutically active agents to be added to the compositions compared to known ophthalmic compositions. This is possible, for example, if the active is soluble (or at least partially soluble) in the discontinuous phase (preferably the oil phase) of the polyaphron dispersion. The polyaphron dispersion can have a higher level of oil than other compositions, for example, and still remain stable despite the inclusion of an emulsion.

The ophthalmic compositions described herein also allow for effective, preferably improved, delivery of pharmaceutically active agents and/or additives to the eye. This can be achieved by increasing the permeability.

In the case of a pharmaceutically active agent present in the composition, preferably after 3 months of storage, each active should not decrease more than 5% by weight over the original content at the date of the start of the storage test, the known decomposition products of the active (if any) together constitute no more than 5% of the original active, based on the area under curve measurement, e.g. by HP L C analysis or other suitable analysis techniques known in the art.

Preferably, the ophthalmic compositions described herein have at least one or more of the following advantages over known ophthalmic compositions, e.g., it helps to improve patient compliance:

a) convenience (e.g., reducing the frequency of administration by formulating combinations of pharmaceutically active agents);

b) efficacy (e.g., improved permeability to increase effect at unaltered concentrations or to maintain effect at lower concentrations); and

c) safety (better tolerability, e.g. by reducing irritating excipients and/or pharmaceutically active agents in the formulation).

In addition, the ophthalmic compositions described herein achieve the described benefits while having low levels of surfactants. This is advantageous because surfactants can be irritants.

In the following description, the terms used have the following meanings: by hydrophilic phase or solvent is meant a liquid phase comprising water, comprising water and other water-soluble liquids, or comprising water-miscible, anhydrous liquids. By hydrophobic phase or solvent is meant a phase comprising a pharmaceutically acceptable liquid, such as an oil which is immiscible or substantially immiscible with the hydrophilic phase. Immiscible liquids means that when mixed together they separate to form two distinct liquid phases that share a well-defined interface. By substantially immiscible it is meant that the two liquids mixed as described above have a well-defined interface between the two phases, however, each of the phases may have dissolved molecules of the other phase in small amounts.

The polyaphron dispersion includes a continuous phase, a discontinuous phase, and a surfactant. It will be understood that a typical polyaphron dispersion comprises one continuous phase and a plurality of discontinuous phases. The polyaphron dispersion can include a hydrophobic discontinuous phase, and a hydrophilic continuous phase. Alternatively, the polyaphron dispersion may comprise a hydrophilic discontinuous phase, and a hydrophobic continuous phase.

As used herein, polyaphron dispersion means a particular class of hydrophilic liquid dispersion in a hydrophobic liquid or hydrophobic liquid dispersion in a hydrophilic liquid, which includes (a) a hydrophilic liquid miscible phase, (b) a second hydrophobic phase that is immiscible or substantially immiscible with the first phase, and (c) one or more surfactants, wherein the dispersed or discontinuous phase is in the form of small (e.g., micron to submicron diameter, but more typically at least 1 micron diameter) droplets, which are whole (whole) having characteristics that distinguish polyaphron dispersions from conventional or common polyaphron emulsions and other dispersion types:

1. they can exist in a stable form, in which the volume fraction (Φ) of the dispersed phase_ip) Greater than 0.7 and can be as high as 0.97 (phi)_ipIs the volume ratio of the discontinuity to the continuous phase expressed as a fraction).

2. Wherein phi_ipThe microscopic morphology of the polyaphron dispersion of greater than 0.7 is agglomerates (agglomerates) of individual droplets while tightly extruding into a polyhedral shape, similar to the morphology of bubbles. In this form, theThe dispersion has gel-like properties and is known as a Gel Polyaphron Dispersion (GPD).

3. Stable polyaphron dispersions can be formed from surfactant concentrations of less than 3% by weight, more typically less than 2% by weight of the total composition.

4. When the gel-like properties disappear, the gel polyaphron dispersion (as described in 2 above) can be diluted to any extent by adding more continuous phase, but not more surfactant. At phi_ipAfter dropping below 0.7, the individual droplets of the internal phase separate to take the form of spherical droplets, which remain stable and intact, however, they can bind together in a weak association (association) and float to the top of the diluted dispersion or sink to the bottom of the diluted dispersion (depending on the relative densities of the two phases). in this diluted form, each droplet is referred to as a colloidal liquid foam (C L a). simple shaking of the diluted dispersion immediately produces a uniform, stable colloidal liquid foam dispersion for reconstitution.

Each of the above features and their combinations clearly distinguish the polyaphron dispersions of the invention from conventional emulsions and other dispersion types (not all of those features). Polyaphron dispersions are disclosed in the following references: sebba, "double fooms", J.colloid and Interface Science,40(1972)468-,257(1979)392-,131(1998)119-136. Foams are also disclosed in US-A-4,486,333 and WO 97/32559.

Polyaphron dispersions are sometimes referred to as "biliquid foams", "High Internal Phase Emulsions (HIPEs)", "high internal phase ratio emulsions (HIPEs)" and "gel emulsions". In US 5,573,757, a composition comprising a polyaphron dispersion is described as a "viscoelastic gel". All descriptions relating to dispersions having the above characteristics are of the polyaphron dispersions used in the present invention.

The terms "topical composition" and "topical formulation" are used interchangeably herein. When a topical composition comprises an active ingredient, it refers to a composition that is prepared such that the active ingredient of the composition can be administered by direct administration to the surface of the eye, and that releases an amount of the active ingredient from the composition. Examples of topical formulations include, but are not limited to, lotions, sprays, hydrogels, aerosols, foams, ointments, creams, gelling agents, pastes, and the like. The term "topical" when used herein to characterize the delivery, administration, or application of a composition of the present invention means that the composition is delivered, administered, or applied directly to the site of interest (i.e., the eye) for a localized effect. Preferably, the local administration is performed without any significant absorption of the components of the composition into the bloodstream of the subject (to avoid systemic effects). In certain preferred embodiments of the invention, topical administration of the composition is carried out without any significant absorption of the components of the composition into the ocular tissues of the subject (e.g., aqueous humor, corneal tissue and conjunctival tissue).

Preferably, the composition is administered directly to the cornea and/or slowly instilled into the anterior portion of the eye. The composition can be administered to achieve therapeutic benefits to other parts of the eye, for example, to goblet cells, lacrimal glands, oil secreting glands, and/or nasolacrimal duct.

As used herein, the term "non-invasive" refers to an administration method or mode in which the delivered composition, optionally including a pharmaceutically active agent, is incapable of rupturing or puncturing (e.g., by mechanical means) a biological membrane. Preferably, the ophthalmic compositions described herein are administered by a non-invasive route or procedure.

As used herein in connection with compositions, the term "ophthalmic" refers to compositions that are administered to the eye, preferably, which preferentially provide a pharmaceutical effect to the eye.

The terms "therapeutic agent," "drug," and "pharmaceutically active agent" are used interchangeably herein. They refer to a substance, molecule, compound, agent, factor or composition that is effective in the treatment of a disease or disorder.

The ophthalmic compositions described herein may be formulated with any pharmaceutically acceptable carrier and/or excipient suitable for topical administration to the surface of the eye.

In one embodiment, the ophthalmic compositions described herein are not used for tear replacement therapy, as a tear substitute, or in a tear substitute solution. In one embodiment, the ophthalmic compositions described herein are used to treat ocular diseases, provided that they are not used to treat "dry eye". Preferably, the ophthalmic compositions described herein comprise a pharmaceutically active agent and are useful in the treatment of diseases of the human and/or animal eye, which diseases can be treated by topical administration of the pharmaceutically active agent.

As described above, the polyaphron dispersion includes a continuous phase, at least one discontinuous phase, and a surfactant. The polyaphron dispersion can include a hydrophobic discontinuous phase (typically a plurality of hydrophobic discontinuous phases), and a hydrophilic continuous phase. Alternatively, the polyaphron dispersion may comprise a hydrophilic discontinuous phase (typically a plurality of hydrophilic discontinuous phases), and a hydrophobic continuous phase.

Preferably, the discontinuous phase comprises a hydrophobic solvent and the continuous phase comprises a hydrophilic solvent. Preferably, the discontinuous phase is a hydrophobic discontinuous phase comprising one or more hydrophobic solvents and being substantially free of hydrophilic solvents. Preferably, the continuous phase is a hydrophilic continuous phase comprising one or more hydrophilic solvents and being substantially free of hydrophobic solvents. Typically, there are multiple discontinuous phases present in the composition.

In another embodiment of the present invention, the continuous phase comprises a hydrophobic solvent and the discontinuous phase comprises a hydrophilic solvent. Preferably, the continuous phase is a hydrophobic continuous phase comprising one or more hydrophobic solvents and being substantially free of hydrophilic solvents. Preferably, the discontinuous phase is a hydrophilic discontinuous phase comprising one or more hydrophilic solvents and being substantially free of hydrophobic solvents. Typically, there are multiple discontinuous phases present in the composition.

Preferably, the discontinuous phase is a substantially hydrophobic internal phase, commonly referred to as the oil internal phase. Preferably, the hydrophobic phase, which is the preferred discontinuous phase, comprises a pharmaceutical oil phase.

Examples of oils that may be used in the present invention include: almond oil, babassu oil, blackcurrant seed oil, borage oil, rapeseed oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard oil, oat oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower seed oil, walnut seed oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, isopropyl myristate, isopropyl isostearate, isopropyl palmitate, modified triglycerides (modified triglycerides), caprylic/capric glycerides, tricaprylin/tricaprin, fractionated triglycerides, tricaprin, tricaprylin, Tricaprylin/tricaprin, tricaprin/trilaurin, tricaprylin/tricaprin/triolein, tricaprylin/tricaprin/tristearin, trilaurin, triolein, trilinolein, triolein, tristearin, glycerol tris (undecanoate), glycerol linoleate, saturated polyglycolyzed glycerides, synthetic medium chain triglycerides containing predominantly C8-C12 fatty acid chains, medium chain triglycerides, long chain triglycerides, modified triglycerides, fractionated triglycerides, silicones, phospholipids, and mixtures thereof.

Long chain triglycerides described herein include glycol triesters in which the acid moiety is a saturated, monounsaturated or polyunsaturated fatty acid having a chain of 14 to 20 carbon atoms. Typically, the fatty acid moieties are oleic acid, stearic acid, and linoleic acid.

Suitable hydrophobic phases include one or more monoglycerides, diglycerides, triglycerides or mixtures thereof. Preferably, the one or more monoglycerides, diglycerides, triglycerides are glycol esters of fatty acids containing from 6 to 22 carbon atoms.

In a preferred embodiment, the hydrophobic phase is selected from the group consisting of: castor oil, long chain triglycerides, medium chain triglycerides, mineral oil, silicones, phospholipids, monoglycerides and diglycerides and mixtures of two or more thereof.

More preferably, the composition comprises omega-3 fatty acids are long chain polyunsaturated fatty acids (containing 18-22 carbon atoms in the chain length) having a first double bond ("unsaturated") starting at the third carbon atom from the methyl end of the molecule, they are referred to as "polyunsaturated" because their molecules have more than two double bonds "unsaturated" in their carbohydrate chain, they are referred to as "long chain" fatty acids because their carbon backbone (backbone) has at least 18 carbon atoms, except for linoleic acid "SDA", the omega-3 family of fatty acids includes α -linolenic acid ("a L a"), eicosatetraenoic acid (ETA), eicosapentaenoic acid ("EPA"), docosapentaenoic acid (DPA), and docosahexaenoic acid ("DHA").

Preferably, the ophthalmic composition does not comprise a fluorocarbon and/or silicone oil.

The discontinuous phase may, for example, impart lubrication, occlusion, moisturization, accommodation, or other cosmetic or pharmaceutical benefits to the eye. It may also increase the viscosity of the composition and may impart solubility to one or more actives. When applied to the eye, it may contain a material that provides a heating or cooling effect (e.g., capsaicin or menthol).

The composition may comprise at least 5% by weight of the discontinuous phase, more preferably at least 2% by weight of the discontinuous phase, based on the weight of the total composition.

The composition may comprise less than 15% by weight of the discontinuous phase, more preferably less than 5%, less than 4%, less than 2%, less than 1%, less than 0.5% by weight of the discontinuous phase, based on the weight of the total composition. Unlike topical compositions for the skin, which advantageously have a high level of discontinuous phase (preferably an oily phase), in the ophthalmic compositions described, it is advantageous in certain embodiments to include a much lower level of discontinuous phase. Because the eye is very sensitive, low levels of active agent are generally sufficient to treat eye conditions when the active agent is present in the composition. One advantage of using polyaphron dispersions is that, unlike emulsions, a low percentage of discontinuous phase (such as those described above) can be present in the composition and can still be stable. Polyaphron dispersions are resistant to high levels of dilution. Preferably, the discontinuous phase comprises a medicinal oil.

The hydrophilic phase (which may be a continuous phase) may comprise or consist essentially of a pharmaceutically acceptable liquid which is miscible with or substantially miscible with water, preferably of formula R₁-OH, wherein R₁Is C₁-C₁₀Alkyl and/or of the formula OH-R₂A compound of formula (I) -H, wherein R₂Is- (C)₂H₄) n or- (C)₃H₆) n, wherein n is 1 to 100, preferably 1 to 25. R₁And R₂And may be linear or branched. Preferably R₁Is C₁-C₄An alkyl group. Preferably, n is 1 to 25. Preferably, the hydrophilic phase comprises propylene glycol, polyethylene glycol, glycerol, ethanol, isopropanol, or mixtures thereof. Wherein the hydrophilic phase comprises polyethylene glycol or polypropylene glycol, preferably the polyethylene glycol or polypropylene glycol is a polyethylene glycol that is liquid at room temperature (20 ℃). For example, the polyethylene glycol may contain 1 to 12 ethylene oxide or propylene oxide units and/or have a molecular weight of up to 600.

It will be appreciated that other suitable hydrophilic solvents may be used.

The composition may comprise at least 95% by weight of the continuous phase, more preferably at least 98% by weight of the continuous phase, based on the weight of the total composition.

Preferably, the ophthalmic composition comprises water. Preferably, the hydrophilic phase is or comprises water. The compositions of the present invention may be anhydrous, substantially anhydrous, or aqueous.

The term "anhydrous" as used herein means a composition that is substantially free of water and does not contain specifically added water. Preferably, an "anhydrous" composition as used herein has less than 0.5% by weight water, more preferably less than 0.2% by weight water, based on the total weight of the composition, most preferably less than 0.1% by weight water, based on the total weight of the composition.

The term "substantially anhydrous" as used herein means a composition comprising less than 5% by weight, more preferably less than 4.5% by weight, of water, based on the total weight of the composition.

The term "aqueous" means a composition that includes at least 5%, at least 10%, or at least 15% water by weight, based on the total weight of the composition.

In one embodiment, the composition comprises at least 85% by weight water, at least 90% by weight water, at least 95% by weight water or at least 98% by weight water, based on the total weight of the composition. Compositions comprising high levels of water may be advantageous if the composition is administered to the eye without further dilution. In addition, having a high level of water reduces the potential risk of irritation to the eye caused by other components present in the composition.

Suitable pharmaceutical excipients may be present in the composition.

The pH of the composition and preferably the pH of the hydrophilic phase (which is preferably the continuous phase) is preferably from 3.5 to 9, or from 5 to 8, still more preferably from 6 to 7.5. It will be appreciated that any suitable acid or base may be used to adjust the pH to the appropriate value or pH range. Preferably, the pH of the hydrophilic phase is adjusted as desired after addition of the hydrophobic phase. The pH of the composition can be adjusted after the polyaphron dispersion is added. Typically, it will be necessary to raise the pH of the composition by the addition of a base, which may suitably be sodium hydroxide. Advantageously and preferably, the pH of the composition can be stabilized by incorporating a suitable buffer into the aqueous phase. Suitable buffer systems having a pH within the specified range, e.g. comprising a sodium citrate buffer, will be well known to the person skilled in the art.

The surfactants used in the present invention may be incorporated into either or both phases of the polyaphron dispersion. The surfactant may be selected from the group consisting of a nonionic surfactant, a cationic surfactant, an anionic surfactant, a zwitterionic surfactant, and a mixture of two or more thereof.

In one embodiment, preferably, the polyaphron dispersion comprises at least one nonionic surfactant. Preferably, at least one nonionic surfactant is present in the hydrophilic and/or hydrophobic phase of the present invention. The polyaphron dispersion may further comprise a non-ionic and/or an ionic surfactant.

Suitable surfactants include alkyl polyglycol ethers, alkyl polyglycol esters, ethoxylated alcohols, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, ionic or nonionic surfactants, hydrogenated castor oil/polyoxyethylene glycol adducts having from 25 to 60 ethoxylations, castor oil/polyoxyethylene glycol adducts having from 25 to 45 ethoxylations, sorbitan fatty acid esters (e.g., span 20 or span 80), block copolymers of ethylene oxide and propylene oxide (e.g., Pluronic L121 or Pluronic F68), or mixtures thereof.

Suitable nonionic surfactants include poloxamers, tyloxapol, polysorbates, polyoxyethylene castor oil derivatives, sorbitan esters, and mixtures of two or more thereof.

Suitable cationic surfactants include cetyltrimethylammonium bromide, CTAB and mixtures of two or more thereof.

Suitable anionic surfactants include sodium lauryl ether sulfate (S L ES), sodium lauryl sulfate, and mixtures of two or more thereof.

Suitable zwitterionic surfactants include: such as phospholipids, e.g., lecithin, dipalmitoylphosphatidylcholine (DpPC), and mixtures of two or more thereof.

Preferably, the compositions of the present invention do not comprise fluorinated surfactants. Preferably, the compositionSurfactants containing fluorine atoms are not included. Still more preferably, the compositions described herein do not comprise fluorinated surfactants prepared according to the general formula: r_F-R_polWherein R is_FRepresents a linear or branched perfluorinated alkyl group having more than 5 carbon atoms, R_polRepresents a polar hydrocarbon residue comprising at least one functional group selected from the following series: CO-NH (R), CO-NH (R)₂、COO-、COOR、SO₃-、SO₂-N(R)₂、CH₂-O-、R、PO₂H、PO₃H₂Wherein R represents an alkyl group.

Preferred surfactants are nonionic, non-halogenated surfactants. It has been found that polyaphron dispersions comprising nonionic halogenated surfactants (particularly those mentioned above) can be broken down under shear stress caused by the blinking of the eyelids (causing irreversible breakdown of polyaphrons) when the composition is in place in the eye. This is particularly the case when the polyaphron dispersion is formed by a gas foam intermediate. In contrast, the present inventors have unexpectedly discovered that nonionic, non-halogenated surfactants and/or polyaphron dispersions prepared using the methods described below, which do not require the formation of a gas foam intermediate, do not generally decompose under shear stress caused by the blinking of the eyelid when the composition is in place in the eye. This is shown in figure 1. In some cases, it is advantageous that the composition and surfactant remain intact under the shear stress conditions generated by the eye. This is particularly the case when the composition includes a pharmaceutically active agent. When the composition comprises a pharmaceutically active agent, one advantage of the present invention is that the active agent can be released from the ophthalmic composition in a controlled manner, for example, by diffusion from a polyaphron dispersion (typically by diffusion from a hydrophobic, preferably oil phase). If the polyaphron dispersion breaks down under shear conditions generated by the eye, the pharmaceutically active agent is not delivered in a controlled manner over time. Conversely, the active is suddenly released into the eye because the polyaphron dispersion irreversibly breaks down. In contrast, it is preferred to release the active in a controlled manner over time. Another advantage of polyaphron not disintegrating under shear is that the risk of damage to the composition during transport and storage is reduced.

A further advantage of polyaphron dispersions that do not disintegrate (or substantially do not disintegrate) under conditions generated by the eye is that the risk of precipitation of any pharmaceutically active agent dissolved and/or dispersed therein is reduced. For example, if a pharmaceutically active agent is dissolved and/or dispersed in a discontinuous phase of a composition, preferably a hydrophobic phase (preferably an oil phase), the composition and the polyaphron are broken down under shear conditions generated by the eye, which may precipitate as the pharmaceutically active agent rapidly flows from the polyaphron dispersion into the eye. The risk of precipitation is reduced by the controlled release of a pharmaceutically active agent from the polyaphron dispersion, wherein the active agent remains intact within the eye.

Examples of classes of surfactants particularly useful in the present invention include: polyethylene glycol sorbitan fatty acid esters (tweens, e.g., tween 20 (polyethylene glycol (20) monolaurate), tween 60 (polyethylene glycol (20) monostearate), tween 80 (polyethylene glycol (20) monooleate)); sorbitan fatty acid esters (spans, e.g., span 20 (sorbitan monolaurate), span 40 (sorbitan monopalmitate), span 80 (sorbitan monooleate)); polyethylene glycol fatty acid esters (Brij's, e.g., Brij 35 (polyoxyethylene (20) lauryl ether), Brij 58 (polyoxyethylene (20) cetyl ether)); polyethylene glycol stearate (Mryj, e.g., Mryj S40 (polyoxyethylene (40) stearate), Myrj S50 (polyoxyethylene (50) stearate)); polyoxyethylene glycol (polyoxyyethylene glycol) -block-polypropylene glycol-block-polyoxyethylene glycol-block (poloxamers, such as polyoxyethylene glycol (80) -polypropylene glycol (27) -polyoxyethylene glycol (80) (poloxamer 188) and polyoxyethylene glycol (101) -polypropylene glycol (56) -polyoxyethylene glycol (101) (poloxamer 407)) polyethylene glycol lauryl ester (laureth, e.g., polyethylene glycol (4) lauryl ester (laureth 4) and polyethylene glycol (23) lauryl ester (laureth 23)), and mixtures of two or more thereof. One or more surfactants of each type may be present in the composition. Additionally or alternatively, mixtures of different types of surfactants may be present in the composition. One reason for the particular preference of these surfactants is because of their low irritating efficacy. The present inventors have also unexpectedly found that the above surfactants provide good shear stability relative to other known surfactants.

It will be appreciated that other suitable surfactants may be used.

Preferably, the compositions of the present invention comprise less than 0.5% by weight of the total composition of surfactant, more preferably less than 0.25%, still more preferably less than 0.1% by weight. The compositions described herein may comprise less than 0.075% by weight or less than 0.05% by weight or 0.01% by weight of surfactant, based on the weight of the total composition.

Preferably, the polyaphron dispersion used in the described compositions comprises less than 5% by weight of surfactant, based on the total weight of the polyaphron dispersion. More preferably, the polyaphron dispersion comprises less than 3%, less than 2%, or less than 1% by weight of surfactant, based on the total weight of the polyaphron dispersion. Typically, to form the compositions described, the polyaphron dispersion is diluted, for example, by from about 80%, 90%, or 95% by weight of the discontinuous phase (preferably the oil phase) based on the total composition (which is herein a polyaphron dispersion) to about 1%, 2%, or 5% by weight of the discontinuous phase (preferably the oil phase) based on the total composition. Thus, the surfactant level in the final composition is generally low.

As noted above, low levels of surfactant in the composition are desirable because, after use in the eye, the surfactant can act as a stimulus to the end user.

Preferably, the weight ratio of the discontinuous phase (which is preferably the hydrophobic phase) in the composition to the total surfactant in the composition is from 40 to 180. More preferably, the weight ratio of the discontinuous phase (which is preferably a hydrophobic phase) in the composition to the total surfactant in the composition is from 50 to 120. Still more preferably, the weight ratio of the discontinuous phase (which is preferably a hydrophobic phase) in the composition to the total surfactant in the composition is from 60 to 90.

The use of low levels of surfactant is advantageous for at least the following reasons:

1. during use, it is less likely to cause irritation to the eye itself and to the area around the eye that is contacted with the formulation;

2. there is more effective use of any preservative in the composition because it is not encapsulated by micelles formed by excess surfactant. In turn, this results in less eye irritation (preservatives have a large number of possible irritants); and/or

3. Is less likely to cause the separation and delivery of oil soluble pharmaceutically active agents into surfactant micelles, avoiding solubility-related events and stability associated with labile pharmaceutically active agents.

Preferably, the pharmaceutically active agent is selected from the group consisting of antihistamines, β -blockers, corticosteroids, prostaglandins, non-steroidal anti-inflammatory drugs (NSAIDs), immunomodulators, anesthetics, antibiotics, carbonic anhydrase inhibitors, vasoconstrictors, and mixtures of two or more thereof.

In addition to the pharmaceutically active agents listed above, additionally and/or alternatively, the pharmaceutically active agent may be selected from the group consisting of: antifungal agents, ophthalmic drugs, anti-infective agents, anti-inflammatory agents, anti-glaucoma miotic agents, mydriatic agents, cycloplegic agents, decongestants, antiallergic agents, local anesthetics, diagnostic agents, surgical aids, ocular vascular disorder agents, and mixtures of two or more thereof. One or more pharmaceutically active agents of each type may be present in the composition. Additionally or alternatively, mixtures of different types of pharmaceutically active agents may be present in the composition.

Optionally, the composition of the invention may further comprise at least one additional pharmaceutically active substance or agent.

The composition may comprise more than two specific discontinuous phases consisting of different components, e.g. different oils. In certain discontinuous phases, the composition may include one or more pharmaceutically active substances or agents.

The pharmaceutically active agent may be present in the hydrophilic and/or hydrophobic phase of the polyaphron dispersion. In one embodiment, at least 50%, at least 80%, or at least 90% by weight of the pharmaceutically active agent present in the composition is in the hydrophilic phase. In another embodiment, at least 50%, at least 80%, or at least 90% by weight of the pharmaceutically active agent present in the composition is in the hydrophobic phase.

Preferably, the ophthalmic composition comprises cyclosporin. Such compositions may be advantageous because they may be formulated as non-irritating compositions. Such compositions are suitable for the treatment of conditions associated with keratoconjunctivitis sicca (severe dry eye).

Cyclosporin a, and some other smaller metabolites, as well as cyclosporins B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, and z, have been identified and derivatives, salts, etc. of such cyclosporins, as well as a number of synthetic analogs, have been prepared and may be used in the present invention.

In general, commercial cyclosporins may contain a mixture of several individual cyclosporins, all having a cyclic peptide structure consisting of eleven amino acid residues, having an overall molecular weight of about 1,200, but with different substitutions or structures of certain amino acids.

As used herein, "cyclosporine" includes any individual member of the cyclosporine group, salts, derivatives, analogs, and mixtures thereof, as well as mixtures of two or more of their individual cyclosporines, salts, derivatives, analogs, and mixtures thereof.

In one embodiment, the cyclosporine includes cyclosporine a, a derivative of cyclosporine a, a salt of cyclosporine a, and/or a mixture thereof.

Cyclosporin A has the chemical name cyclo [ [ (E) - (2S,3R,4R) -3-hydroxy-4-methyl-2- (methylamino) -6-octenoyl (octenoyl) ] -L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl ]. formula 1 represents the chemical structure of Cyclosporin A.

As used herein, the term "derivative" of cyclosporine refers to a compound having a structure sufficiently similar to cyclosporine to function in a manner substantially similar or substantially identical to cyclosporine a.

Without limitation, useful derivatives of cyclosporin a include those selected from the group consisting of: ((R) -methylthio-sarcosine (Sar))³- (4' -hydroxy-methylleucine) cyclosporin A, ((R) - (cyclo) alkylthio-sarcosine (Sar))³- (4' -hydroxy-methylleucine)⁴-Cyclosporin A, and ((R) - (cyclo) alkylthio-sarcosine (Sar))³-cyclosporin a derivatives.

These cyclosporin derivatives are represented by the following general formulae (II), (III), and (IV), respectively:

wherein Me is methyl; alk is C2-6 alkylene or C3-6 cycloalkylene; r is OH, COOH, alkoxycarbonyl, -NR₁R₂Or N (R)₃)-(CH₂)-NR₁R₂(ii) a Wherein R is₁、R₂Is H, alkyl, C3-6 cycloalkyl, phenyl (optionally substituted byHalogen, alkoxy, alkoxycarbonyl, amino, alkylamino, or dialkylamino substituted), benzyl, or a saturated or unsaturated heterocyclic group having a 5-or 6-membered ring and 1-3 heteroatoms; or NR₁R₂Is a 5 or 6 membered heterocyclic ring which may further contain N, O, or an S heteroatom and which may be alkylated; r₃Is H or alkyl, and n is 2-4; and the alkyl portion contains C1-4.

In one embodiment of the invention, the composition does not include cyclosporine (e.g., cyclosporine a or a cyclosporine derivative or cyclosporine salt).

In one embodiment of the invention, the composition does not comprise vitamin D and/or vitamin D analogues and/or corticosteroids.

Preferably, the ophthalmic composition comprises hyaluronic acid and/or a pharmaceutically acceptable salt and/or derivative thereof.

In one embodiment, an ophthalmic composition comprises cyclosporin and hyaluronic acid and/or pharmaceutically acceptable salts and/or derivatives thereof.

Preferably, the ophthalmic composition comprises flurbiprofen and/or pharmaceutically acceptable salts and/or derivatives thereof.

Ophthalmic compositions may include vancomycin, fluticasone, latanoprost, cyclosporine, ketotifen, propranolol, flurbiprofen, clotrimazole, pharmaceutically acceptable salts of any of the foregoing, derivatives of any of the foregoing, and mixtures of two or more thereof.

Examples of suitable actives for use in the compositions described herein for the treatment of specific conditions are given below.

Species of active	Examples of actives	Disorders of the disease
			β -adrenoceptor blockers	Ketotifen	Glaucoma treatment
Immunosuppressant	Cyclosporin	Dry eye
			Prostaglandin	Latanoprost	Glaucoma treatment
Anti-histamines	Propranolol (Propranolol)	Allergic conjunctivitis
			Antibiotic	Vancomycin	Bacterial infection, chalazion and hordeolum
Corticosteroids	Fluticasone	Inflammation of eye, blepharitis, Behcet's disease, uveitis

For any of the pharmaceutically active agents or pharmaceutically active drugs described herein, pharmaceutically acceptable salts, isomers, esters, derivatives, and bases thereof may be substituted. Mixtures of pharmaceutically active agents may be used in which the agent is therapeutically effective.

Preferably, the ophthalmic compositions of the present invention are present in unit dosage forms. Each unit dose may comprise from 0.0025mg to 500mg, specifically from 1mg to 100mg, of the pharmaceutically active agent. It will be understood that the preferred unit dose will depend upon the particular pharmaceutically active agent used, or the particular combination of pharmaceutically active agent and method of administration of the dose used.

When the compositions described herein include a pharmaceutically active agent, the pharmaceutically active agent is preferably present in an effective amount. As used herein, the term "effective amount" refers to any amount of a compound, agent, or composition sufficient to achieve its intended purpose (e.g., a desired biological or medical response in a tissue, system, or subject). For example, in certain embodiments of the invention, the purpose may be: slowing or stopping the progression, exacerbation, or worsening of symptoms of the disease or disorder of the eye, alleviating symptoms of the disease or disorder, and/or curing the disease or disorder. Determination of an effective amount is well known to those of ordinary skill in the pharmaceutical sciences and medicine, i.e., it may depend on a variety of biological factors or individual differences, as well as on response to treatment.

The term "pharmaceutically acceptable carrier or excipient" refers to a carrier medium that does not interfere with the effectiveness of the biological (or pharmaceutical) activity of the active ingredient and, preferably, does not have undue toxicity to the subject at the concentrations administered.

The composition can comprise additives such as inert diluents, buffering agents, dispersing or wetting agents, preservatives, chelating agents, antifoaming agents, antioxidants, permeation enhancers, gelling agents, rheology modifiers (e.g., viscosity modifiers), tonicity agents, and combinations of one or more thereof. These additives may be included in the continuous and/or discontinuous phase of the polyaphron dispersion and/or may be added to the composition after the polyaphrons are formed.

The inert diluent may be sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate.

Examples of buffering agents include citric acid, acetic acid, lactic acid, hydrogenophosphoric acid, diethylamine, sodium hydroxide, and tris (hydroxymethyl) aminomethane (i.e., tris- (hydroxymethyl) aminomethane hydrochloride).

Examples of dispersing or wetting agents are naturally occurring phosphatides (e.g., lecithin or soya lecithin), condensation products of ethylene oxide with fatty acids or with long chain fatty alcohols (e.g., polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate).

Preservatives may be added to the compositions of the present invention to prevent microbial contamination, which may affect the stability of the formulation and/or cause infection in the patient. Suitable examples of preservatives include parabens (e.g., methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, and isopropyl paraben), potassium sorbate, sorbic acid, benzoic acid, methyl benzoate, phenoxyethanol, bronopol (bronopol), 5-bromo-5-nitro-1, 3-dioxane (bronidox), MDM hydantoin, iodopropynyl butyl carbamate, benzalkonium chloride (benzalkonium chloride), cetyltrimethylammonium bromide, and benzyl alcohol. Preferred preservatives include benzalkonium chloride, benzalkonium bromide ("benzalkonium bromide"), "Purite" (stabilized oxychloro complex), methylparaben, butylparaben, propylparaben, and mixtures of two or more thereof.

Preferably, the composition comprises less than 0.05% by weight of preservatives, based on the total weight of the composition. More preferably, the composition comprises less than 0.02%, less than 0.01%, or less than 0.005% by weight of a preservative, based on the total weight of the composition.

Examples of chelating agents include sodium EDTA and citric acid.

Anti-foaming agents, which generally facilitate the preparation of pharmaceutical compositions, defoam by destabilizing the air-liquid interface and allowing liquid to drain from the bubbles. Examples of defoaming agents include simethicone, dimethicone, ethanol, and ether.

Suitable antioxidants include, but are not limited to, Butylated Hydroxyanisole (BHA), butylated hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate, α -tocopherol, ascorbic acid, retinoic acid, lutein, derivatives, precursors or prodrugs thereof, and mixtures of two or more thereof.

One or more penetration enhancers may be added to the composition to facilitate, for example, delivery to the back of the eye.

Suitable penetration enhancers include propylene glycol. Other suitable ocular penetration enhancers may be selected from one or more mixtures from the following non-exhaustive list:

the surfactant is sorbitan glyceride (span 20, span 40, span 85), polyoxyethylene sorbitan glyceride (Tween 20, Tween 40, Tween 81), polyethylene glycol 1000 stearate (Aptet 100), G1045, polyoxyethylene stearyl ether (Brij 23, Brij 35, Brij 48, Brij 58, Brij 78, Brij 98), polyoxyethylene stearate (Myrj S40, Myrj S50), polyoxyethylene castor oil (Cremophor E L), B L-9, polyoxyethylene p- (tetramethylbutyl) phenyl ether (Triton X-100), and saponin;

bile acids and bile salts: deoxycholic acid; taurocholic acid; taurodeoxycholic acid; ursodeoxycholic acid; tauroursodeoxycholic acid; sodium cholate; sodium glycocholate;

fatty acid: capric acid;

preservative: benzalkonium chloride; benzalkonium bromide (dodecyl dimethyl ammonium bromide, benzododecinium bromide); chlorhexidine digluconate; benzyl alcohol; chlorobutanol; 2-phenyl ethanol; esters of p-hydroxybenzoic acid; propyl p-hydroxybenzoate;

chelating agent: EDTA;

others 1-dodecylazacycloheptan-2-one (azone), hexamethylene lauramide, hexamethylene octanoamide, dodecylmethyl sulfoxide, Pharmasolve (N-methylpyrrolidone), Gelucire44/14 (lauryl polyethylene glycol-32 glyceride), borneol, dimethyl sulfoxide, sodium fusidate, decahydrocarbonium bromide (decamethonium bromide), cetylpyridinium chloride, α -amino acids, cyclodextrins, medium chain monoglycerides, cetyltrimethylammonium bromide, cytochalasin.

Particularly preferred penetration enhancers are Brij 58, azone, β -cyclodextrin, cetyltrimethylammonium bromide, and mixtures of two or more thereof.

The ophthalmic composition may include one or more tonicity agents. Suitable tonicity agents include one or more of sorbitol, glycerin, sodium chloride, and dextrose.

The tonicity agent may be selected from the group consisting of salts, sugars, sugar alcohols, glycols, ureas, and mixtures of two or more thereof. Suitable salts include sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, sodium pyruvate, sodium ascorbate, and mixtures of two or more thereof. Suitable sugars include glucose, sucrose, fructose, xylose, mannose, and mixtures of two or more thereof. Suitable sugar alcohols include sorbitol, mannitol, xylitol, maltitol, sorbitan, and mixtures of two or more thereof. Suitable glycols include glycerin, propylene glycol, and mixtures thereof. Suitable ureas include urea. One or more tonicity agents of each type may be present in the composition. Additionally or alternatively, mixtures of different types of tonicity agents may be present in the composition.

In certain embodiments, a tonicity agent will be present in an amount that renders the composition (preferably a solution or liquid) hypertonic. Hypertonic solutions have an osmotic pressure greater than that of isotonic solutions. Typically, when a hypertonic composition is added to the eye, water can seep out of the eye. This can cause stinging, which in some cases should be avoided.

A hypotonic composition, preferably a solution, has a lower osmotic pressure than an isotonic composition, preferably a solution or liquid. Typically, hypotonic ophthalmic compositions (preferably solutions or liquids) cause less irritation than hypertonic compositions.

Compositions can be selected that are substantially isotonic with, for example, human and/or animal tears. The isotonic composition (preferably a solution or liquid) has an osmotic pressure substantially equal (preferably equal) to that of the other side of the semipermeable membrane. For example, it is generally believed that 0.9% sodium chloride is approximately isotonic with human tears. The osmolality of 0.9% w/w NaCl was 290 mOsm/kg. This is isotonic with the blood and most cells in the human body.

Preferably, the compositions described herein are approximately isotonic.

Preferably, the composition (preferably in solution or liquid form) has an osmolality of 200 to 600mOsm/kg, more preferably in the range of 240 to 400mOsm/kg, even more preferably in the range of 280 to 320 mOsm/kg.

The osmolality of the composition can be varied by adjusting the amount of tonicity agent present in the composition.

Osmolality was determined by freezing point depression using a suitable automated apparatus such as an Advanced Instruments Inc Model 3320 osmometer.

As outlined above, the composition of the present invention may further comprise one or more gelling agents and/or rheology modifiers, such as viscosity modifiers, and mixtures of two or more thereof.

The gelling agent may be pH sensitive (e.g., carbomer) or heat sensitive (e.g., polyethylene glycol or poly (N-isopropylacrylamide)). The gelling agent may include one or more polysaccharides (e.g., carrageenan, mucopolysaccharide, or starch). The gelling agent may comprise one or more cellulose or water-soluble cellulose derivatives. The gelling agent may comprise one or more clays.

For example, the gelling agent may be selected from guar gum, locust bean gum, xanthan gum, gum arabic, cellulose or water-soluble cellulose derivatives (such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose or their salts), mucopolysaccharides (such as hyaluronic acid), clays (such as bentonite), magnesium aluminum silicate, "carbomers" (salts of crosslinked polymers of acrylic acid), or glyceryl polymethacrylates or their dispersions in ethylene glycol. It will be appreciated that other suitable gelling agents may be used. In addition, the present inventors have discovered that certain gelling agents (e.g., carbomers) can also act as chemical buffers, thus preventing adverse changes in the pH of the composition during storage and use.

Preferably, the composition of the present invention comprises from 0.01 to 1.0% by weight of the total composition of a gelling agent, preferably from 0.02 to 0.5% by weight, more preferably from 0.05 to 0.25% by weight.

It will be appreciated that these additives will be included at levels determined to be effective and useful, as well as the type of material determined to be effective and useful.

In another aspect, the invention provides methods of treatment for ocular diseases and conditions, particularly ocular diseases and conditions that infect the surface of the eye, such as inflammatory conditions. Such methods typically include the following steps: topically administering to the ocular surface of the subject an effective amount of a composition of the invention.

According to an embodiment, the ophthalmic composition described herein is preserved. According to another embodiment, the ophthalmic compositions described herein of the present invention are not preserved.

According to an embodiment, the ophthalmic composition of the present invention is present in a disposable unit.

According to another embodiment, the ophthalmic compositions of the present invention are marketed in multi-dose containers.

The present invention also relates to medicaments comprising the ophthalmic compositions described herein.

The ophthalmic composition may be a cosmetic composition and/or it may be used in cosmetic applications.

Preferably, the ophthalmic compositions described herein have a viscosity of from 1 to 50Pas, more preferably from 10 to 40 Pas. The viscosity can be determined using a cone-plate rheometer at a temperature of 37 ℃ and a shear rate of 1/s. An example of a suitable cone-plate rheometer for measuring the viscosity of a composition is Bohlin CVO 120. Preferably, the viscosity of the composition is such that it can be readily administered to the eye by topical application (e.g., by dropper).

Preferably, the average diameter of the foam droplets is 0.5 to 50 μm, more preferably in the range of 1 to 20 μm, more preferably in the range of 2 to 10 μm. The average diameter of the droplets (or bubbles) can be determined by fraunhofer (fraunhofer) diffraction laser scattering (e.g. malvern mastersizer 2000) or by optical microscopy.

Preferably, the volume average droplet size of the discontinuous phase droplets (preferably oil droplets) is less than 60 μm, more preferably less than 50 μm, more preferably less than 40 μm. Volume average droplet (or bubble) size can be determined using fraunhofer diffraction laser scattering (e.g., malvern mastersizer 2000) or by optical microscopy.

The structural integrity of the polyaphron dispersion and/or the polyaphron dispersion in the composition or product can be assessed using a droplet size distribution analyzer, such as a Malvern Mastersizer analyzer, which measures the particle size distribution by small angle laser diffraction.

In one aspect of the present invention, there is provided an ophthalmic composition described herein for use in the treatment of the human and/or animal eye by topical administration.

In one embodiment, the ophthalmic compositions described herein can be used to treat glaucoma, dry eye, allergic conjunctivitis, bacterial infection, chalazion, hordeolum, ocular inflammation, blepharitis, behcet's disease, uveitis, and mixtures of two or more thereof, e.g., by topical administration.

In another embodiment, the ophthalmic compositions described herein can be used in the preparation of a medicament that can be used, for example, by topical administration, for the treatment of glaucoma, dry eye, allergic conjunctivitis, bacterial infections, chalazion, hordeolum, ocular inflammation, blepharitis, behcet's disease, uveitis, and mixtures of two or more thereof.

The ophthalmic compositions described herein may be in the form of eye drops and/or gels for administration to the eye. The ophthalmic composition may be a liquid or a solution.

Preferably, e.g. at 25 ℃, preferably at more than 300s^-1The viscosity of the liquid is less than 1Pas, measured at a shear rate of (c). Preferably, the liquid is capable of flowing and takes the form of a container.

The ophthalmic composition may be used as an eye bath solution or liquid. Ophthalmic compositions may be in the form of a dilutable solution or liquid.

In one embodiment, the composition is in the form of a gel, wherein at least a portion of the gel is liquefied after application to the eye and during blinking of the eyelids. Thus, the liquefied composition may be distributed, preferably evenly distributed, on the eye.

Preferably, the compositions described herein do not comprise moulded bodies of polymer matrix (such as those described in WO 2009/001099). Preferably, the ophthalmic compositions described herein cannot be molded (preferably by solution-gel conversion) into a desired shape. Rather, preferably, the composition is in the form of a liquid, preferably a free-flowing liquid. Preferably, it is not capable of solution-gel transition. Preferably, the compositions described herein are not in the form of, or for use with, eye patches. As will be understood by those skilled in the art, the eye shield is a small pad worn in front of the eye. Preferably, the compositions described herein are for use in direct contact with one or more components of the eye, not designed for use on the eyelid (as designed for the eye mask). The composition described in WO 2009/001099 behaves as a viscoelastic solid with a high degree of viscoelasticity, which breaks up without flowing when deformed by the applied pressure. Thus, the formulation described in WO 2009/001099 will not flow and spread on the eye. Thus, the formulation described in WO 2009/001099 is not suitable for application to the eye. Instead, they will only be suitable for use with an eye patch on the eye, pre-shaped and non-flowing in use.

In contrast, in the present invention, the composition is preferably designed such that, after the composition is applied to the eye, the polyaphron droplets flow and spread on the eye under shear stress generated by the eye (e.g., by blinking). This is because, preferably, these formulations are highly shear diluted (thining), preferably viscoelastic liquids. Estimated shear rate in the eye during blinking is about 300 to 500s^-1. Preferably, e.g. at 25 ℃, preferably at more than 300s^-1The viscosity of the composition is less than 1Pas, measured at a shear rate of (c).

In one embodiment of the present invention, there is provided the use of an ophthalmic composition described herein in the manufacture of a medicament for the treatment of an ocular disorder, e.g., dry eye or severe dry eye.

It will be understood that the ophthalmic compositions described herein are suitable for administration to human and/or animal eyes. Preferably, the composition is sterile and/or sterilized.

According to one aspect of the present invention, there is provided a method of preparing an ophthalmic composition as described herein, comprising the steps of:

(i) providing a hydrophilic solvent;

(ii) providing a hydrophobic solvent;

wherein the hydrophilic solvent and/or the hydrophobic solvent comprises a surfactant.

Ophthalmic compositions may be prepared under sterile and/or sterile conditions. The ophthalmic composition may be autoclaved to sterilize the composition. The ophthalmic composition may be exposed to gamma radiation to sterilize the composition.

A typical autoclaved composition will be subjected to high pressure saturated steam (e.g., at a pressure of about 100 kpa) for about 10 to 20 minutes at about 110 to 140 ℃, or 120 to 135 ℃. Suitable conditions may be to sterilize the composition in an autoclave for about 15 minutes at 121 ℃ after preparation. Suitable conditions will depend on the loading and content. An example of a suitable autoclave is the Prestige Model 21004 Portable autoclave or the Prestige Optima B Class autoclave.

The inventors have unexpectedly found that polyaphron dispersions are substantially resistant to autoclaving. In other words, the polyaphron dispersions substantially maintain their physical integrity during and after autoclaving. In contrast, it has been found that emulsions are typically adversely affected by autoclaving. Without wishing to be bound by any particular theory, it is believed that this difference is a result of the different interactions of the surfactants in the emulsion and polyaphron dispersion with respect to the continuous and discontinuous phases. It is believed that in emulsions, the nature of the surfactant interaction with the continuous and discontinuous phases is more sensitive to changes in temperature (specifically increases). Autoclaving can be carried out at elevated temperatures, for example at temperatures above 110 ℃, above 120 ℃, or above 130 ℃. Autoclaving is generally carried out at 121 ℃ or 126 ℃. Under these conditions, the emulsion is likely to become unstable and the emulsion can separate (or begin to separate) into a hydrophobic layer and a hydrophilic layer. In contrast, in polyaphron dispersions, the surfactant is more closely and stably associated with the discontinuous phase of the dispersion. For this reason, polyaphron dispersions are generally considered to be much more physically stable and less likely to separate into distinct phases than emulsions. It is particularly advantageous to be able to autoclave a composition, as will be appreciated, for administration to the eye should be sterile to avoid infection. One advantage of autoclaving the composition is that the composition may avoid the use of preservatives and/or may reduce the amount of preservatives required.

Advantageously, it has also been unexpectedly found that the average diameter of the foam droplets changes by less than 10%, preferably less than 5%, more preferably less than 2% after autoclaving.

Preservatives can be added to the compositions as outlined above. The addition of preservatives is particularly advantageous if autoclaving is not used. Preservatives are added to preserve the composition, which is typically prepared under sterile conditions in a suitable state for use and to prevent, for example, bacterial growth. The present inventors have surprisingly found that the use of polyaphron dispersions rather than emulsions enables the level of preservative to be used to be reduced. In order for the emulsion to remain stable, the level of surfactant present needs to be higher than in the equivalent amount of polyaphron dispersion. The present inventors have found that when higher levels of surfactant are required, higher levels of preservative are required to maintain the same antimicrobial effect. Advantageously, for a number of reasons: for example, the cost of preparing the composition is reduced; reducing the risk of irritation caused by the preservative after application of the composition to the eye; and/or reduce the risk of undesired interaction of the preservative with any active agent or component of the composition, using lower levels of preservative while also preserving the composition.

Optionally, the hydrophilic solvent and/or the hydrophobic solvent comprises one or more pharmaceutically active agents.

Suitable processes for preparing polyaphron dispersions are described in US-A-4486333 and EP 1469940. One skilled in the art will appreciate that other methods of preparation may be used, as appropriate.

Unexpectedly, the present inventors have found that by using the process for preparing polyaphron dispersions described herein and outlined in EP 1469940 is advantageous over the process for preparing polyaphron dispersions by the foaming process such as those previously described by SebbA (e.g. those described in US-A-4486333). Unstable formulations can be formed using foaming methods such as those described in Sebba. Without wishing to be bound by any particular theory, it is believed that this is related to the droplet size distribution produced by the foaming process. Preferably, the polyaphron dispersion is formed without the formation of a gas foam intermediate.

According to another aspect of the present invention, there is provided a method of preparing an ophthalmic composition as described herein, comprising the steps of:

preparing a first polyaphron dispersion optionally comprising a pharmaceutically active agent;

preparing a second polyaphron dispersion optionally comprising a pharmaceutically active agent;

and mixing the first and second polyaphron dispersions together to form a composition.

The method may further comprise:

preparing a third or further polyaphron dispersion, optionally comprising additives such as inert diluents, buffering agents, dispersing or wetting agents, preservatives, chelating agents, antifoaming agents, antioxidants, gelling agents, penetration enhancers, tonicity agents, and combinations of one or more thereof;

and mixing the third or further polyaphron dispersion with the first and second polyaphron dispersions to form a composition.

Additives such as inert diluents, buffers, dispersing or wetting agents, gelling agents, preservatives, chelating agents, antifoaming agents, antioxidants, gelling agents, permeation enhancers, tonicity agents, and combinations of one or more thereof can be added to the hydrophilic and/or hydrophobic solvent prior to forming the polyaphron dispersion. Additionally and/or alternatively, additives such as inert diluents, buffering agents, dispersing or wetting agents, gelling agents, preservatives, chelating agents, antifoaming agents, antioxidants, permeation enhancers, gelling agents, tonicity agents, and combinations of one or more thereof can be added to the composition after the polyaphron dispersion is formed.

The ophthalmic composition may comprise more than one polyaphron dispersion. Each polyaphron dispersion can be comprised of one or more different materials to the other polyaphron dispersions in the ophthalmic composition. Each polyaphron dispersion may include the same or a different pharmaceutically active agent (preferably within the discontinuous phase of the polyaphron dispersion).

According to one embodiment of the present invention, there is provided a method of preparing an ophthalmic composition as described herein, comprising the steps of: (i) providing a polyaphron dispersion, and (ii) mixing the polyaphron dispersion with a pharmaceutically active agent. Preferably, the pharmaceutically active agent is dissolved and/or at least partially dissolved in the solvent. Preferably, the pharmaceutically active agent is dissolved and/or at least partially dissolved in the hydrophilic solvent.

According to another embodiment of the present invention, there is provided a method of preparing an ophthalmic composition as described herein, comprising the steps of: (i) at least partially dispersing and/or dissolving a pharmaceutically active agent in a hydrophobic solvent; (ii) mixing the hydrophobic solvent including the pharmaceutically active agent with at least one hydrophilic solvent and at least one surfactant under suitable conditions to form a polyaphron dispersion.

As outlined above, it will be understood that the ophthalmic compositions described herein are suitable for administration to human and/or animal eyes. Typically, this means that the composition is sterile and/or sterilized.

The ophthalmic compositions described herein can be prepared under sterile and/or aseptic conditions such that the resulting ophthalmic compositions are sterile and/or aseptic. Additionally and/or alternatively, the ophthalmic composition may be formed under sterile and/or sterilized conditions, and/or under non-sterilized and/or non-sterilized conditions and subsequent processing to produce a sterile and/or sterilized product. Preferably, the method of preparing the ophthalmic composition described herein further comprises autoclaving the ophthalmic composition. In particular, the present inventors have discovered that ophthalmic compositions described herein comprising a polyaphron dispersion can be autoclaved under suitable conditions to form compositions suitable for administration to the eye of a human and/or animal. Suitable autoclaving conditions are known to those skilled in the art. Typically, autoclaving is carried out at about 121 ℃.

In one aspect of the present invention, there is provided an ophthalmic composition described herein for use as a medicament. In particular, there is provided an ophthalmic composition as described herein for the prophylactic or therapeutic treatment of human and/or animal eyes.

In one aspect of the invention, there is provided a device for the dropwise dispensing of a composition, the device comprising a container holding a composition as described herein.

In one embodiment of the present invention, there is provided a method of treating the eye of a human and/or animal comprising administering to the eye an ophthalmic composition described herein. The ophthalmic composition may be administered to the eye drop by drop. The composition may be administered using a dropper or may be poured into the eye.

In a preferred embodiment, the ophthalmic composition comprises a polyaphron dispersion, a pharmaceutically active agent, and a cationic surfactant. Preferably, it also comprises a buffer and/or an inert diluent.

In another preferred embodiment, the ophthalmic composition comprises a polyaphron dispersion, a pharmaceutically active agent, and a non-ionic surfactant. Preferably, it also comprises a buffer and/or an inert diluent.

When introducing elements of the present disclosure or the preferred embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

The terms "about" and "approximately" as used herein in reference to a number generally includes the number within plus or minus (greater or less than the number) 10% of the number (except where such number would exceed the possible value), unless otherwise indicated or otherwise clear from the context.

The foregoing detailed description is provided by way of explanation and illustration, and is not intended to limit the scope of the appended claims. Many variations of the preferred embodiments described herein will be apparent to one of ordinary skill in the art and are within the scope of the appended claims and their equivalents.

Drawings

The invention will now be further described, by way of example only, with reference to the accompanying drawings, in which:

fig. 1 is a graph showing apparent viscosity (pa.s) versus shear rate for the composition described in example 3.

Detailed Description

The following non-limiting examples will further illustrate the invention.

Examples

Example 1

Gel polyaphron dispersions of the following compositions were prepared by the following method.

Final product	％w/w
		Gel polyaphron dispersions	2.24
0.2% polyacrylic acid (carbomer 980, Noveon)	95.56
		Glycerol	2.20
NaOH, adjusted to pH 7.0 to 7.4	Proper amount of

Cyclosporine a content in the final formulation was 500 μ g/g. The final product had an osmolality in the range of 250-320 mOsm/kg.

Preparation method

Preparing a polyaphron dispersion by:

a low-profile, 250ml laboratory beaker (6.5 cm internal diameter) was charged with sufficient aqueous (continuous) phase to prepare 30g of gelled microvesicles. The oil (discontinuous) phase was added dropwise with a pasteur pipette while stirring at 200rpm using a four-bladed propeller (four-bladed propeller) with a diameter of 6.0 cm. The addition rate was slow at the start of the process (about one drop per 7 seconds), but once 10% of the oil phase was added, accelerated so that the total time to prepare the gelled microbubbles was about 20 minutes.

The active was dissolved in the appropriate phase by gentle stirring with a magnetic stirrer overnight in a covered beaker at room temperature prior to preparation of the gel polyaphron dispersion.

To form the final product, the microvesicles were mixed with carbomer gel and glycerol, and the pH was adjusted to the desired pH by adding NaOH solution (20% w/w).

The formulations were loaded into suitable containers and sterilized by autoclaving (121 ℃, 15 minutes).

Stability measurement

Stability measurements were performed using the methods outlined below.

Cyclosporin was extracted from the composition of example 1 into acetonitrile and analyzed by HP L C under the conditions given below.

HP L C Condition

Column: NovaPak C8, 4 μm particle size, 3.9X 150mm column (Waters)

Mobile phase: 75% v/v acetonitrile, 25% v/v 5mM PO4 buffer, pH 5.1.

Flow rate: 1 ml/min.

Column temperature: at 50 ℃.

Injection volume: 1 μ l.

Detector wavelength: 205 nm.

The retention time of cyclosporine was 3.0 minutes.

The inventors observed that after 3 months of storage at 40 ℃, the level of cyclosporin was 102% ± 3% of the original level.

Permeability of cyclosporin through the cornea

In order to determine the permeability of cyclosporin (CsA) preparations into and through the cornea, in vitro studies were performed. Briefly, corneas from rabbits were harvested and placed in Ussing diffusion cells incubated at 37 ℃ and pre-perfused with carbopol (95/5 oxygen/carbonic acid). Approximately 3ml of sample was placed on the donor side of the chamber (champer) and 3ml of ringer's solution (6.5g NaCl, 0.42g KC1, 0.25g CaCl)₂And 1 mole of sodium bicarbonate per liter; isotonic solution pH 7.2) was placed on the receptor side of the chamber.

At appropriate time points, permeability through the cornea was determined by collecting 200 μ l of the receptor phase at times 0 and 8 hours (termination of the test), 100 μ l samples from the donor phase were taken for analysis, the cornea was collected and separated into a stromal (stomal) fraction and an epithelial fraction, cyclosporine in the corneal fraction was analyzed after extraction into 50/50 methanol/water, CsA levels in the receptor compartment, cornea and donor compartment were determined by HP L C analysis.

In the FN # summary 1, the FN # s,

1. same as example 1

2. As in example 1, 1% w/w Tween 20 (polyoxyethylene (20) sorbitan monolaurate) was added

3. Carbomer-free, 0.01% benzalkonium chloride (BAC)

4. Castor oil substituted for medium chain triglycerides

5. In the same way as example 1, 1% of Brij 58 (polyoxyethylene (20) cetyl ether) was added

Typical alternatives to the formulation:

benzalkonium chloride

Results

The total amount of CsA (cyclosporine a) found in the cornea and transcorneal into the receptor compartment is summarized below.

Flow is not correlated with time, so no data is given.

From these data, the following conclusions can be drawn:

the presence of 1.1% brij 58 has a significant positive effect on the penetration of CsA into the cornea.

2. Less good permeability was observed from the use of castor oil as a carrier for lipophilic CsA.

3. The use of tween 20 had a slightly adverse effect on the penetration of CsA into and through the cornea.

4. The presence of benzalkonium chloride had no significant effect on CsA penetration.

Example 2

Gel polyaphron dispersions
		Oil phase	％
Flurbiprofen solution in castor oil (Fluka) ((7.0%))	89.10
		Laureth-4 (Volpo L4-Croda)	0.90

		Aqueous phase
Poloxamer 188 (Pluronic F68-BASF)	0.50
		Demineralized water	9.50

Final product	％w/w
		Gel polyaphron dispersions	0.48
0.2% polyacrylic acid (carbomer 980, Noveon)	95.32
		Sorbitol (Sigma)	4.20
NaOH, adjusted to pH 7.0	Proper amount of

Flurbiprofen content in the final formulation was 300 μ g/g. The final product had an osmolality in the range of 250-320 mOsm/kg.

Preparation method

The procedure used was exactly as described in example 1 above.

Stability measurement

Stability measurements were performed using the methods outlined below.

Flurbiprofen was extracted from the composition of example 1 into acetonitrile and determined by HP L C under the conditions given below.

HP L C conditions:

column: NovaPak C18, 5 μm particle size, 3.9X 100mm column (Waters)

Mobile phase: 65% v/v acetonitrile, 35% v/v 0.1mM sodium acetate, pH 6.3.

Flow rate: 1 ml/min.

Column temperature: at 25 ℃.

Injection volume: 25 μ l.

Detector wavelength: 248 nm.

The retention time of flurbiprofen was 4.5 minutes.

The inventors observed that after 3 months of storage at 40 ℃, the level of flurbiprofen was 98% ± 2% of the original level.

Example 3

Final product	％w/w
		Gel polyaphron dispersions	2.00
0.1% polyacrylic acid (carbomer 980)	93.10
		Sorbitol (CxPharmsorbosodex P, S Black)	4.90
NaOH, adjusted to pH 6.7	Proper amount of

Latanoprost content in the final formulation was 50 μ g/g. The final product had an osmolality in the range of 250-320 mOsm/kg.

Preparation method

Preparing a polyaphron dispersion by:

a low-profile, 250ml laboratory beaker (6.5 cm internal diameter) was charged with sufficient aqueous (continuous) phase to prepare 30g of gelled microvesicles. The oil (discontinuous) phase was added dropwise with a pasteur pipette while stirring at 200rpm using a four-bladed propeller with a diameter of 6.0 cm. The addition rate was slow at the start of the process (about one drop per 7 seconds), but once 10% of the oil phase was added, accelerated so that the total time to prepare the gelled microbubbles was about 20 minutes.

The active (liquid at room temperature) was mixed with the appropriate phase by gentle stirring with a magnetic stirrer in a covered beaker at room temperature before the preparation of the gel polyaphron dispersion. The dispersion of the active in the oil phase takes less than 30 minutes.

Stability measurement

Stability measurements were performed using the methods outlined below.

Latanoprost was extracted from the composition of example 3 into acetonitrile, determined by HP L C under the conditions given below.

HP L C conditions:

the instrument comprises the following steps: acquity H Class (Waters)

Column: BEH C18, 1.7 μm particle size, 2.1X 50mm column (Waters) and VanGuard C18 guard column (Waters)

Mobile phase: 70% v/v acetonitrile, 30% v/v water.

Flow rate: 0.5 ml/min.

Column temperature: at 40 ℃.

Injection volume: 10 μ l.

Detector wavelength: 210 nm.

The retention time of latanoprost was 0.4 minutes.

The formulations were dispensed into autoclavable dropper vials and the samples were sterilized by holding at 121 ℃ for 15 minutes using standard procedures of a Prestige autoclave. An indicator tape was used to ensure an autoclave sterilization cycle.

The inventors observed that the level of latanoprost was 99.4% ± 0.1% of the level in the untreated sample after autoclaving the formulation.

Shear test

Comparison of apparent viscosity versus shear rate for carbomer stabilized eye drop formulations (using example 3). Included shear rates range from 0.1 to 500/s. After 5 minutes of standing, the same samples were subjected to the same shear rate protocol. The results are shown in fig. 1. There was no significant difference between the two viscosity maps, indicating that high shear non-permanently affected the structure of this formulation.

Method of producing a composite material

Rheological measurements were made using a Bohlin CVO 120 rheometer controlled shear rates were applied to the sample (approximately 2g) through a 40mm diameter stainless steel cone and plate shape, the cone angle was 4 °, the temperature was held at 25 ℃.

Example 4

Final product	％w/w
		Gel polyaphron dispersions	2.00
0.1% polyacrylic acid (carbomer 980)	93.10
		Glucose (Anhydrous D-glucose, Fisher)	4.90
NaOH, adjusted to pH 6.7	Proper amount of

Preparation method

Polyaphron dispersions were prepared as in example 3.

Stability measurement

Stability measurements were performed using the methods outlined below.

Latanoprost was extracted from the composition of example 4 into acetonitrile, determined by HP L C under the conditions given in example 3.

The inventors observed that the level of latanoprost after autoclaving the formulation was 83.7% ± 0.4% of the level in the untreated sample.

In contrast to example 3, in this example, the use of osmolality of the glucose-regulated formulation resulted in the production of an unstable formulation.

Example 5

Final product	％w/w
		Gel polyaphron dispersions	2.00
0.1% polyacrylic acid (carbomer 980)	93.05
		Polyethylene glycol (20) stearyl ester (Acros)	0.05
Sorbitol (CxPharmsorbosodex P, S Black)	4.90
		NaOH, adjusted to pH 6.7	Proper amount of

Content of fluticasone in the final formulation was 50 μ g/g. The final product had an osmolality in the range of 250-320 mOsm/kg.

Preparation method

Preparing a polyaphron dispersion by:

The active was dissolved in the appropriate phase by gentle stirring with a magnetic stirrer in a covered beaker at room temperature prior to preparation of the gel polyaphron dispersion. Dissolution of the active in the oil phase took about 2 hours.

Example 6

Final product	％w/w
		Gel polyaphron dispersions	2.00
0.1% polyacrylic acid (carbomer 980)	95.50
		Glycerol (Fisher)	2.50
NaOH, adjusted to pH 6.7	Proper amount of

Vancomycin content in the final formulation was 30 μ g/g. The final product had an osmolality in the range of 250-320 mOsm/kg.

Preparation method

Polyaphron dispersions were prepared as in example 3.

Example 7

Final product	％w/w
		Gel polyaphron dispersions	2.24
0.2% xanthan gum (Aldrich)	95.56
		Glycerol	2.20
NaCl	0.10
		NaOH, adjusted to pH 7.0 to 7.4	Proper amount of

Preparation method

Preparing a polyaphron dispersion by:

Prior to preparation of the gel polyaphron dispersion, the active was dissolved in the appropriate phase by gentle stirring overnight using a magnetic stirrer in a covered beaker at room temperature.

To form the final product, the microbubbles are dispersed in water. Sodium chloride was added as a solution. The required amount of xanthan gum was dispersed in glycerol before adding the diluted microvesicles. The pH of the formulation was adjusted to pH 6.50 to 7.00 using NaOH or HCl.

The formulations were loaded into suitable containers and sterilized by autoclave (121 ℃, 15 minutes).

Example 8

Gel polyaphron dispersions
		Oil phase	％
Ketotifen solution in soybean oil (Aldrich) (5.10%)	89.10
		Laureth-4 (Volpo L4-Croda)	0.90

		Aqueous phase
Polysorbate 80 (Tween 80, Sigma)	0.50
		Demineralized water	9.50

Final product	％w/w
		Gel polyaphron dispersions	1.10
0.1% polyacrylic acid (carbomer 980)	93.05
		Polyethylene glycol (20) stearyl ester (Acros)	0.05
Sorbitol (CxPharmsorbosodex P, S Black)	4.9
		NaOH, adjusted to pH 6.7	Proper amount of

Ketotifen content in the final formulation was 250 μ g/g. The final product had an osmolality in the range of 250-320 mOsm/kg.

Preparation method

Polyaphron dispersions were prepared by the method described in example 1.

Example 9

Propranolol content in the final formulation was 2.5 mg/g. The final product had an osmolality in the range of 250-320 mOsm/kg.

Preparation method

Polyaphron dispersions were prepared as in example 1.

Before addition of xanthan and locust bean gum, microvesicles were dispersed into water by stirring at 260 rpm. The gum is added as a pre-dispersed suspension in glycerol. Stirring was continued until a gel structure was formed, approximately 10 minutes.

Example 10

Final product	％w/w
		Gel polyaphron dispersions	4.50
0.2% polyacrylic acid (carbomer 980)	90.60
		Sorbitol (CxPharmsorbosodex P, S Black)	4.90
NaOH, adjusted to pH 7.0 to 7.4	Proper amount of

Clotrimazole content in the final formulation was 1000 μ g/g. The final product had an osmolality in the range of 250-320 mOsm/kg.

Preparation method

Polyaphron dispersions were prepared by the method described in example 1.

The invention will now be described with respect to the following non-limiting items:

1. an ophthalmic composition comprising a polyaphron dispersion.

2. The ophthalmic composition of item 1, comprising a pharmaceutically active agent.

3. The ophthalmic composition of item 2, wherein said pharmaceutically active agent is selected from the group consisting of antihistamines, β -blockers, corticosteroids, prostaglandins, non-steroidal anti-inflammatory drugs (NSAIDs), immunomodulators, anesthetics, antibiotics, carbonic anhydrase inhibitors, vasoconstrictors, and mixtures of two or more thereof.

4. The ophthalmic composition of any one of the preceding items, wherein the pharmaceutically active agent comprises cyclosporine.

5. The ophthalmic composition according to any one of the preceding items, comprising omega-3 fatty acids.

6. The ophthalmic composition according to any one of the preceding items, wherein the composition has a pH of from 3.5 to 9, preferably from 5 to 8, more preferably from 6 to 7.5.

7. The ophthalmic composition of any one of the preceding items, comprising a gelling agent.

8. The ophthalmic composition according to any one of the preceding items, having a viscosity of 1 to 50 Pas.

9. The ophthalmic composition according to any of the preceding items, comprising a surfactant selected from the group consisting of non-ionic surfactants, cationic surfactants, anionic surfactants, zwitterionic surfactants, and mixtures of two or more thereof.

10. The ophthalmic composition according to any of the preceding items, comprising a pharmaceutically acceptable oil selected from the group consisting of castor oil, long chain triglycerides, medium chain triglycerides, mineral oil, silicones, phospholipids, monoglycerides and diglycerides, and mixtures of two or more thereof.

11. An ophthalmic composition according to any one of the preceding items for use in the treatment of human and/or animal eyes by topical administration.

12. The ophthalmic composition according to any one of the preceding items, in the form of eye drops and/or a gel to be administered to the eye.

13. The ophthalmic composition according to any one of the preceding items, wherein the average diameter of the droplets of the foam is from 0.5 to 50 μ ι η.

14. A method of making an ophthalmic composition according to any one of the preceding items, comprising the steps of:

(i) providing a hydrophilic solvent;

(ii) providing a hydrophobic solvent;

(iii) mixing the hydrophilic solvent with the hydrophobic solvent under suitable conditions to form the composition comprising a polyaphron dispersion;

wherein the hydrophilic solvent and/or the hydrophobic solvent comprises a surfactant;

and wherein the hydrophilic solvent and/or the hydrophobic solvent optionally comprises a pharmaceutically active agent.

15. The method of clause 14, which is performed under sterile and/or aseptic conditions.

16. The method of clauses 14 or 15, further comprising autoclaving the ophthalmic composition.

17. A device for dropwise dispensing of a composition, the device comprising a container holding a composition as defined in any one of the preceding items.

Claims

1. A sterile and/or sterilized ophthalmic composition comprising:

a polyaphron dispersion comprising less than 15%, by weight of the composition, of a hydrophobic discontinuous phase; and a hydrophilic continuous phase comprising less than 0.5%, by weight of the ophthalmic composition, of a surfactant;

wherein the composition does not comprise a fluorinated surfactant,

wherein the composition comprises at least one non-ionic, non-halogenated surfactant,

wherein the composition is in the form of eye drops, and

wherein the polyaphron dispersion remains intact under shear stress caused by blinking of the eyelid of the patient when the composition is in position within the eye of the patient.

2. The ophthalmic composition of claim 1, which is in liquid form.

3. The ophthalmic composition of claim 1 or claim 2, comprising a pharmaceutically active agent.

4. The ophthalmic composition of claim 3, wherein said pharmaceutically active agent is selected from the group consisting of antihistamines, β -blockers, corticosteroids, prostaglandins, non-steroidal anti-inflammatory drugs, immunomodulators, anesthetics, antibiotics, carbonic anhydrase inhibitors, vasoconstrictors, and mixtures of two or more thereof.

5. The ophthalmic composition of claim 1 or claim 2, wherein the composition has an osmolality of 200 to 600 mOsm/kg.

6. The ophthalmic composition of claim 1 or claim 2, comprising a tonicity agent.

7. The ophthalmic composition of claim 6 wherein said tonicity agent is selected from the group consisting of sugars, sugar alcohols, glycols, ureas, and mixtures of two or more thereof.

8. The ophthalmic composition according to claim 1 or claim 2, comprising omega-3 fatty acids.

9. The ophthalmic composition of claim 1 or claim 2, wherein the composition has a pH of 3.5 to 9.

10. The ophthalmic composition of claim 9, wherein the composition has a pH of 5 to 8.

11. The ophthalmic composition of claim 9, wherein the composition has a pH of 6 to 7.5.

12. The ophthalmic composition of claim 1 or claim 2, comprising a gelling agent.

13. An ophthalmic composition according to claim 1 or claim 2, at 1s^-1Has a viscosity of 1 to 50Pas at a shear rate of (2).

14. The ophthalmic composition of claim 1 or claim 2, comprising a medicinal oil selected from the group consisting of: castor oil, long chain triglycerides, medium chain triglycerides, mineral oil, silicones, phospholipids, monoglycerides and diglycerides, and mixtures of two or more thereof.

15. The ophthalmic composition according to claim 1 or claim 2, wherein the at least one non-ionic, non-halogenated surfactant is selected from the group consisting of: polyethylene glycol sorbitan fatty acid esters, polyethylene glycol stearates, polyoxyethylene glycol-block-polypropylene glycol-block-polyoxyethylene glycol-block, polyethylene glycol lauryl esters, and mixtures of two or more thereof.

16. An ophthalmic composition according to claim 1 or claim 2, in the form of a gel for administration to the eye.

17. An ophthalmic composition according to claim 1 or claim 2, wherein the droplets of the microfoam have an average diameter of from 0.5 to 50 μm.

18. An ophthalmic composition according to claim 1 or claim 2 for use in the treatment of human and/or animal eyes by topical administration.

19. An ophthalmic composition according to claim 1 or claim 2 for use in the treatment of the human and/or animal eye by topical administration, wherein the composition is administered directly to the surface of the eye.

20. A method of preparing the ophthalmic composition of claim 1 or claim 2, comprising the steps of:

(i) providing a hydrophilic solvent;

(ii) providing a hydrophobic solvent;

21. The method of claim 20, wherein the hydrophilic solvent and/or the hydrophobic solvent comprises a pharmaceutically active agent.

22. The method of claim 20 or claim 21, which is carried out under sterile and/or sterilized conditions.

23. The method of claim 20 or 21, further comprising autoclaving the ophthalmic composition.

24. A device for dropwise dispensing of a composition, the device comprising a container holding the composition as defined in any one of claims 1 to 19.